Ex Parte Chang

Board of Patent Appeals and Interferences

Mar 30, 2010

11023804 (B.P.A.I. Mar. 30, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte HENG WEI CHANG
__________

Appeal 2009-004009
Application 11/023,804
Technology Center 1600
__________

Decided: March 30, 2010
__________

Before TONI R. SCHEINER, LORA M. GREEN, and FRANCISCO C. PRATS,
Administrative Patent Judges.

SCHEINER, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 from the final rejection of
claims 1-28, directed to a composition for use in a metered dose inhaler.
The claims have been rejected on the grounds of obviousness and lack of
enablement. We have jurisdiction under 35 U.S.C. § 6(b).
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STATEMENT OF THE CASE
Claims 1 and 4 are representative of the subject matter on appeal:
1. A composition for use in a metered dose inhaler (MDI), the
composition comprising predetermined amounts of an active pharmaceutical
ingredient (API) insoluble in the composition, a propellant comprising a
hydrofluoroalkane (HFA), and a pharmaceutically acceptable non-aminated
C1-6 organic carboxylic acid that increases post-shaking suspension time of
the API in the composition to at least 30 seconds to provide uniform dosing
of the API from the inhaler over at least 30 seconds post shaking, wherein
the carboxylic acid is not citric acid or ascorbic acid.

4. The composition of claim 1, wherein the organic carboxylic acid is
selected from the group consisting of lactic acid, 2-methyl propionic acid,
malic acid, maleic acid, acetic acid, butanoic acid, tartaric acid, fumaric acid,
propionic acid, pentanoic acid, succinic acid, oxalic acid, glycolic acid,
hexanoic acid, malonic acid, glutaric acid, formic acid, adipic acid, and
glucuronic acid.

The claims stand rejected as follows:
(A) Claims 1-10, 12, 15-17, 20, and 23-28 under 35 U.S.C. § 112, first
paragraph, as lacking enablement.

(B) Claims 1-28 under 35 U.S.C. § 103(a) as unpatentable over DeStefano1
and Solomons.2

(C) Claims 1-28 under 35 U.S.C. § 103(a) as unpatentable over Keller,3
Solomons, and Brown.4

We affirm rejection (B); and reverse rejections (A) and (C).

1 US 2004/0184994 A1, DeStefano et al., published September 23, 2004.
2 T.W. GRAHAM SOLOMONS, ORGANIC CHEMISTRY 200, 201, 763, 765, 1035
(5th ed. 1992).
3 US 6,585,958 B1, issued July 1, 2003 to Keller et al.
4 THEODORE L. BROWN, CHEMISTRY: THE CENTRAL SCIENCE 628-630, 1016
(6th ed. 1993).
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(A): ENABLEMENT
Issue
Claim 1 is directed to a composition for use in a metered dose inhaler
comprising predetermined amounts of an insoluble active pharmaceutical
agent (API), a hydrofluoroalkane propellant, and a pharmaceutically
acceptable non-aminated C1-6 organic carboxylic acid that increases post-
shaking suspension time of the API to at least 30 seconds, where the
carboxylic acid is not citric acid or ascorbic acid.
According to the Examiner, the “claims are broad and open to an
extremely large range of suspendable . . . active agents” (Ans. 4), but the
Specification doesn’t “provide adequate enabling support for pharmaceutical
aerosol suspensions compositions, wherein the active agent is not albuterol
sulfate, ipratropium bromide, or budesonide; the C1-6 organic acid is not
lactic acid or acetic acid; and wherein the HFA propellant is not HFA 134a
or HFA 227” (id. at 7), “absent an undue quantity of burdensome
experimentation” (id.).
Appellant contends that one need only formulate an MDI composition
using the ingredients and methods disclosed in the Specification, and the
Specification “provides ample guidance on how simple and routine
experimentation is used to determine whether a give formulation has the
required post-shaking suspension stability” (App. Br. 4).
The issue raised by this rejection is: Has the Examiner established
that undue experimentation would have been required to practice the full
scope of the claimed method?

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Findings of Fact
FF1 The Specification teaches that “[a]ny API that has a therapeutic
effect via pulmonary delivery can be used in the composition,” and lists
dozens of APIs compatible with pulmonary delivery (Spec. 6: 13-31). The
API is preferably “micronized to form drug particles of an aerodynamic size
suitable for inhalation into the lungs” (id. at 7: 4-5).
FF2 The Specification discloses at least twenty-four “[e]xemplary
organic acids which increase post-shaking suspension time of diverse APIs
to provide uniform MDI dosing” (Spec. 3: 19-20).
FF3 The Specification outlines a specific procedure for determining
whether a particular composition has the post-shaking suspension stability
required by the claims (Spec. 8: 29 to 9: 3).
FF4 The Specification’s working examples show that different
combinations and proportions of ingredients provide different degrees of
post-shaking suspension stability (Spec. 8-12).
Principles of Law
“[T]o be enabling, the specification of a patent must teach those
skilled in the art how to make and use the full scope of the claimed invention
without ‘undue experimentation.’” In re Wright, 999 F.2d 1557, 1561 (Fed.
Cir. 1993). “That some experimentation may be required is not fatal; the
issue is whether the amount of experimentation required is ‘undue.’” In re
Vaeck, 947 F.2d 488, 495 (Fed. Cir. 1991). Whether the amount of
experimentation required is undue is determined by reference to the well-
known Wands factors. See In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988).

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Analysis
The Examiner acknowledges that the Specification identifies many
active agents and C1-6 organic acids as suitable for formulating MDI
compositions with the required post-shaking suspension stability. However,
the Examiner finds that the Specification’s examples “are limited to
formulations, wherein the suspended actives are only albuterol sulfate,
ipratropium bromide, or budesonide, the propellants are either HFA 134a or
HFA 227; and the organic acids are only acetic acid or lactic acid” (Ans. 6),
and the examples show that different combinations of ingredients, in
different proportions, produce results that “cannot predictably be determined
with great certainty” (id.). The Examiner’s position is essentially that
producing compositions with the required suspension stability, other than
those specifically exemplified in the Specification’s working examples,
would require “an undue quantity of burdensome experimentation” (id. at 7).
However, the Specification discloses exemplary active pharmaceutical
ingredients (APIs), as well as exemplary organic acids “which increase post-
shaking suspension time of diverse APIs” (Spec. 3: 19-20; Table 1; FF1,
FF2), and describes the procedure for determining whether a particular
composition meets the limitations of the claims (FF3).
In addition, the Specification demonstrates that a certain amount of
variability is observed with different proportions and combinations of
ingredients (FF4). In other words, it’s clear from the Specification that
producing a composition with the required suspension stability is something
of an empirical undertaking. We accept, for the sake of argument, that it
would be time consuming to produce and test multiple HFA-based
compositions with different combinations and proportions of active agents
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and organic acids, and that many of those combinations would not produce a
composition with the required post-shaking suspension stability.
Nevertheless, “[t]he fact that some experimentation is necessary does not
preclude enablement.” PPG Indus., Inc. v. Guardian Indus. Corp., 75 F.3d
1558, 1564 (Fed. Cir. 1996).
The test is not merely quantitative, since a
considerable amount of experimentation is
permissible, if it is merely routine, or if the
specification in question provides a reasonable
amount of guidance with respect to the direction in
which the experimentation should proceed to
enable the . . . practice [of] a desired embodiment
of the invention claimed.

Id. (quoting Ex parte Jackson, 217 USPQ 804, 807 (1982)).
Here, the Examiner doesn’t question the ability of one skilled in the
art to understand and follow the disclosed protocols for making and testing
compositions from the various active ingredients and organic acids disclosed
as suitable. Nor does the Examiner question whether one skilled in the art,
following those protocols, would have obtained some compositions with the
required post-shaking suspension stability.
Given the guidance and direction set forth in the Specification, the
process of making and testing MDI compositions with the properties
required by the claims would require nothing more than routine, iterative
experimentation.
Conclusions of Law
On the facts of this case, we find that the Examiner has not established
that undue experimentation would have been required to practice the full
scope of the claimed method.
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(B): OBVIOUSNESS
Issues
The Examiner rejected claims 1-28 as unpatentable over DeStefano
and Solomons. The issues raised by this rejection are:
Does the evidence of record support the Examiner’s conclusion that it
would have been obvious to substitute a non-aminated C1-6 organic acid,
other than ascorbic acid, for the citric acid in DeStefano’s MDI formulation?
Does the evidence support the Examiner’s conclusion that it would
have been obvious to adjust the amount of organic acid in DeStefano’s
composition from 0.004 % to 0.05%?
Similarly, does the evidence of record support the Examiner’s
conclusion that it would have been obvious to reduce or eliminate the
amount of co-solvent in DeStefano’s composition?
Findings of Fact
FF5 Claim 1 is directed to a composition for use in a metered dose
inhaler comprising predetermined amounts of an insoluble active
pharmaceutical agent (API), a hydrofluoroalkane propellant, and a
pharmaceutically acceptable non-aminated C1-6 organic carboxylic acid that
increases post-shaking suspension time of the API to at least 30 seconds,
where the carboxylic acid is not citric acid or ascorbic acid.
FF6 The composition may also include “a co-solvent, such as
ethanol,” and “minute quantities of water” (Spec. 4: 15, 23).
FF7 According to the Specification, preferred organic acids are
those “identified by the US Food and Drug Administration (FDA) Center for
Food Safety and Applied Nutrition (CFSAN) Priority-based Assessment of
Food Additives (PAFA) Everything Added to Food in the United States
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(EAFUS) list, particularly acids subject to a Generally Recognized As Safe
(GRAS) Notice” (Spec. 3: 13-18).
FF8 Table 1 of the Specification, reproduced below, lists suitable
and effective exemplary organic acids, and includes citric and ascorbic
acids:

FF9 “Typically, the amount of organic acid in the composition is in
the range of 0.001% to 10%, preferably in the range of about 0.01% to 5%,
and most preferably in the range of about 0.1% to 2%” (Spec. 4: 7-9).
FF10 DeStefano discloses a composition for use in a metered dose
inhaler comprising “a small, controlled amount of water” (DeStefano ¶¶ 9,
33), one or more active ingredients, a hydrofluoroalkane propellant, and one
or more excipients (id. at ¶¶ 14-19). The composition is readily dispersible
and provides reproducible dosing (id. at ¶¶ 2, 9, 10).
FF11 According to DeStefano, “[s]uitable excipients . . . include, but
are not limited to: organic acids such as citric acid, lubricants such as oleic
acid, ethanol and carriers” (DeStefano ¶ 11).
FF12 DeStefano discloses formulations containing micronized
albuterol sulphate, ipatropium bromide, 10 % ethanol, water, PVP, HFA
134a, and 0.004 % citric acid (DeStefano ¶¶ 27-29).
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FF13 According to DeStefano, the addition of water improves the
redispersibility of the formulation in the metering chamber, regardless of
“the type of co-solvent, if any, used” (DeStefano ¶ 33).
FF14 The Examiner cites Solomons “to demonstrate that C1-6 organic
acids (e.g. lactic acid and acetic acid) are well known” (Ans. 9).
Principles of Law
The obviousness analysis “need not seek out precise teachings
directed to the specific subject matter of the challenged claim, for a court
can take account of the inferences and creative steps that a person of
ordinary skill in the art would employ.” KSR Int'l Co. v. Teleflex Inc., 550
U.S. 398, 418 (2007). An “[e]xpress suggestion to substitute one equivalent
for another need not be present to render such substitution obvious.” In re
Fout, 675 F.2d 297, 301 (CCPA 1982). As noted by the Court in KSR, “[a]
person of ordinary skill is also a person of ordinary creativity, not an
automaton.” 550 U.S. at 421.
Moreover, “where general conditions of a claim are disclosed in the
prior art, it is not inventive to discover the optimum or workable ranges by
routine experimentation.” In re Aller, 220 F.2d 454, 456 (CCPA 1955).
Analysis
The Examiner finds that DeStefano discloses a readily re-dispersible
formulation for a metered dose inhaler that meets all the limitations of the
claims except that the C1-6 organic carboxylic acid in the formulation is
citric acid, one of the two organic acids excluded from the claims (Ans. 8-
10). Nevertheless, the Examiner concluded that it would have been obvious
to “substitute[ ] other known structurally similar organic acids for citric
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acid,” for example those listed by Solomons, given “DeStefano’s suggestion
that organic acids are suitable” excipients for MDI formulations (id. at 16).
Relying on the Declaration of Heng Wei Chang and Jiang Zhang,5
Appellant contends that DeStefano’s reference to “organic acids such as
citric acid” as suitable excipients is a reference to “a subset of suitable
excipients, i.e. . . . those that are suitable excipients apparent to those of
ordinary skill in the art for use in metered dose inhaler formulations” (Decl.
¶ 4; App. Br. 6). Declarants cite Jinks,6 McNamara,7 DeStefano, and Keller
as evidence that “[t]he organic acids known to those of ordinary skill in the
art as suitable organic acid excipients for use in metered dose inhaler
formulations are citric acid and ascorbic acid” (Decl. ¶ 4). In addition,
Appellant contends that “the cited art does not suggest suitable such
carboxylic acids from the virtually infinite population of possible organic
acids” (App. Br. 7), particularly the group of nineteen organic acids recited
in claims 4, 13, 16, 18, and 25; the acetic acid or lactic acid required by
claims 5, 14, 17, 19, and 27; or the 2-methyl propionic acid or propionic acid
required by claims 22 and 26 (id.).
Appellant’s arguments are not persuasive. DeStefano teaches that
HFA-based MDI formulations can contain “organic acids” as excipients, and
mentions citric acid as an example of the genus of organic acids suitable as
excipients (FF11). The fact that Keller also mentions citric acid, along with

5 Submitted January 3, 2007 under the provisions of 37 C.F.R. § 1.132.
6 International Application WO 02/30394 A2 of Jinks et al., published April
18, 2002.
7 US 6,423,298 B2, issued July 23, 2002 to McNamara et al.
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ascorbic acid, as suitable for use in MDI formulations (see FF16, below),8 is
insufficient to establish that these are the only two organic acids one of
ordinary skill in the art would recognize as suitable organic acid excipients
among the “virtually infinite population of organic acids,” especially given
the evidence of record that citric acid and ascorbic acid, along with
structurally similar organic acids, like lactic acid, acetic acid, and propionic
acid, are “subject to a Generally Recognized As Safe (GRAS) Notice,” and
recognized in the art as safe for consumption (FF7, FF8).
In addition, Appellant contends that claims 21 and 28 require that the
organic acid is present in an amount of 0.01 to 5% (w/w), while the
compositions in DeStefano’s working examples contain 0.004% citric acid
(App. Br. 8). Finally, Appellant contends that the composition of claim 6
comprises a cosolvent, ethanol, in an amount less than 1%, and the
composition of claims 7 and 23-28 is “essentially cosolvent free,” but
“DeStefano contrarily teaches compositions having 10% ethanol . . . and
Solomons does not remedy” this deficiency (id.).
Appellant’s arguments do not persuade us that the Examiner erred.
Again, DeStefano discloses readily re-dispersible MDI formulations
comprising water, at least one active ingredient, at least one HFA propellant,
and one or more excipients, including ethanol and “organic acids such as
citric acid” (FF10, FF11). While the formulations described in DeStefano’s
working examples include 10% ethanol and 0.004% citric acid, the reference
also teaches that the formulations can include one or more of several

8 Appellant has not pointed to anything in particular in the Jinks and
McNamara references, or explained how they support Appellant’s position,
so we have not considered them.
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excipients (FF10, FF11), and the cosolvent, in particular, is optional (FF13).
Appellant has not explained why it would have required anything more than
routine experimentation to determine the optimum or workable ranges for
readily re-dispersible MDI formulations based on the constituents disclosed
by DeStefano, i.e, water, API, HFA, and various excipients including
ethanol and “organic acids such as citric acid.”
Conclusions of Law
The evidence of record supports the Examiner’s conclusion that it
would have been obvious to substitute a non-aminated C1-6 organic acid,
other than ascorbic acid, for the citric acid in DeStefano’s MDI formulation.
The evidence supports the Examiner’s conclusion that it would have
been obvious to increase the amount of organic acid in DeStefano’s
composition from 0.004 % to 0.05%.
Finally, the evidence of record supports the Examiner’s conclusion
that it would have been obvious to reduce or eliminate the amount of co-
solvent in DeStefano’s composition.

(C): OBVIOUSNESS
Issue
The Examiner rejected claims 1-28 as unpatentable over Keller,
Solomons, and Brown.
The issue raise by this rejection is whether the evidence of record
supports the Examiner’s conclusion that it would have been obvious to
include a non-aminated C1-6 organic acid, other than ascorbic acid or citric
acid in Keller’s MDI formulation.

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Findings of Fact
FF15 Keller discloses MDI formulations in the form of suspensions,
emulsions, and solutions comprising one or more active agents, dinitrogen
monoxide, and a hydrofluoroalkane propellant.
FF16 In addition, Keller’s formulations “can contain customary
additives such as cosolvents, glidants or lubricants . . . and surface active
agents” (Keller, col. 10, ll. 12-14), as well as “buffer substances or
stabilizers such as citric acid, ascorbic acid, sodium EDTA, vitamin E, N-
acetylcysteine and the like” (id. at col. 11, ll. 4-6).
FF17 The Examiner cites Brown as evidence that “[t]he requirements
of a buffer are fulfilled by a weak acid-base conjugate pair” such as “acetic
acid/acetate” (Ans. 12).
Analysis
According to the Examiner, “[i]t would have been obvious to . . .
modify Keller’s formulations to utilize another organic acid, because Keller
teaches that the . . . formulations may contain buffering substances. A
person of skill in the art would have been motivated to change the buffering
acid from citric acid or ascorbic acid to another known organic acid, because
these are weak acids and would be expected to exhibit buffering
characteristics” (Ans. 12-13).
We don’t agree with the Examiner’s conclusion that Keller fairly
suggests adding organic acids other than citric and ascorbic acids to MDI
formulations. What Keller suggests is a much broader genus of “buffers and
stabilizers” that happens to include citric and ascorbic acids. This is in
contrast to DeStefano, addressed above, which explicitly states that the
genus of “organic acids such as citric acid” is suitable for use in HFA-based
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MDI formulations (FF11). While Brown might explain what a buffer is and
how it works, Brown discloses many buffers that aren’t organic acids, and
the Examiner doesn’t point to anything in Brown which indicates which
buffers would be acceptable in medicinal compositions like Keller’s.
Conclusions of Law
The evidence of record does not support the Examiner’s conclusion
that it would have been obvious to include a non-aminated C1-6 organic
acid, other than ascorbic acid or citric acid in Keller’s MDI formulation.
SUMMARY
(A) The rejection of claims 1-10, 12, 15-17, 20, and 23-28 under 35 U.S.C.
§ 112, first paragraph, as lacking enablement is reversed.

(B) The rejection of claims 1-28 under 35 U.S.C. § 103(a) as unpatentable
over DeStefano and Solomons is affirmed.

(C) The rejection of claims 1-28 under 35 U.S.C. § 103(a) as unpatentable
over Keller, Solomons, and Brown is reversed.

TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(1)(iv)(2006).

AFFIRMED

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RICHARD ARON OSMAN
3525 DEL MAR HEIGHTS RD. #915
SAN DIEGO, CA 92130